The compound referred to as 12(R)HETE was described as Na.sup.+ -K.sup.+ ATPase inhibitor by Masferrer et al., Inv. Opthal & Vis. Sci 31(3): 535-539 (1990). This reference showed that the referenced compound caused normal intraocular pressure to drop when administered to the eyes of the rabbits. The compound was implicated in control of ATPase levels, as may be seen in, e.g., U.S. Pat. No. 5,102,670 to Abraham et al., the disclosure of which is incorporated by reference. The reference discloses how 12(R)HETE inhibits ocular ATPase, leading to an increase in ocular swelling. The patent presents a method for preventing ocular swelling by inhibiting hemeoxygenase production, as this enzyme leads to increased production of the 12(R)-HETE compound.
Masferrer et al., Biochem. Pharmacol. 39(12): 1971-74 (1990) describe experiments in which partially purified enzyme compositions were tested in combination with 12(R)HETE. In vitro experiments were carried out using renal, cardiac and corneal forms of Na.sup.+ K.sup.+ dependent ATPase. The authors comment, at page 1974 that "(T)he effectiveness of 12(R)HETE in in vitro situations remains uncertain." The paper also describe experiments where 12(R)HETE, ouabain, and combinations of the two drugs were used on corneal and renal enzymes. Table 4 of this paper shows a minimal effect of 12(R)HETE when combined with ouabain, suggesting that whatever mechanism is involved, it is the same for ouabain and 12(R)HETE.
Ouabain is a member of the class of compounds known as the cardiac glycosides. The most well known member of this family of compounds is probably digitalis. These compounds are used in cardiac therapy because of their shared effects on the heart. Specifically, they are implicated in the inhibition of Na.sup.+, K.sup.+ dependent ATPase, and enable more forceful and efficient heart contraction. A problem with therapies involving the regulation of cardiac disorders with the glycosides, however, is that they lead to cardiac arrythmias and conductive defects. If one assumes--as current theory does--that the glycosides lead to increases in intracellular Na.sup.+ levels, this must cause a drop in K.sup.+ levels in order to maintain isosmotic status. Concentrations of K.sup.+ in the Na.sup.+ -K.sup.+ relationship are smaller, however, and when the K.sup.+.sub.[intercellular] /K.sup.+.sub.[intracellular.sub.] ratio changes, intracellular potential is brought to the point where diastolic depolarization--and glycoside induced arrythmias and conductive defects--can and do occur.
Thus, current therapy for heart disorders characterized by inotropic irregularities is faced with a dilemma. While the drugs of choice to appear to inhibit the implicated Na.sup.+, K.sup.+ dependent ATPase, the risk of cardiac arrythmia and conductive defects is great. Useful therapies are sought where the inotropic irregularities can be treated without the risk of cardiac arrythmia and conductive defects.
It has now been found, surprisingly, that the compound 12(R)HETE can be used in vivo to regulate cardiac inotropic irregularities, without the risk of arrythmia. This result is surprising in view of the shared ability of 12(R)HETE and the cardiac glycosides to regulate Na.sup.+ K.sup.+ dependent ATPase, previously thought to be secured via the same mechanism.